N-Acetyl-L-cysteine, C5H9NO3S, is an expectorant. Its synthesis was disclosed in Smith et al., J. Org. Chem., 1961;26:820. N-Acetyl-L-cysteine decreases the viscosity of mucous and purulent expectorate. The mucolytic effect after peroral administration in connection with bronchitis is though not well-documented. However, several investigations have proved effect just below the significance limit. Anyhow, the patients"" wellbeing during treatment with N-Acetyl-L-cysteine is significant. N-Acetyl-L-cysteine is registered as a mucolytic agent for peroral administration under trade marks such as Fabrol(copyright), Inspir(copyright) and Mucomust(copyright).
N-Acetyl-cysteine has a low bioavailability, only about 4-10%, when administered perorally, see Mack R. Holdiness, xe2x80x9cClinical Pharmacokinetics of N-Acetylcysteinexe2x80x9d, Clin. Pharmacokinet., 1991;20(2):123-134. The following references confirm the low bioavailability of N-Acetyl-L-cysteine: L. Borgstrxc3x6m et al., xe2x80x9cPharmacokinetics of N-Acetylcysteine in Manxe2x80x9d, Eur J Clin Pharmacol. 1986;31:217-222, L. Borgstrxc3x6m et al., xe2x80x9cDose dependent pharmacokinetics of N-Acetylcysteine after oral dosing to manxe2x80x9d, Biopharmaceutics and Drug Disposition, 1990(II):131-136, B. Olsson et al., xe2x80x9cPharmacokinetics and Bioavailability of Reduced and Oxidized N-Acetylcysteinexe2x80x9d, Eur J Clin Pharamcol. 1988;34:77-82. Martindale, xe2x80x9cThe Extra Pharmacopoeiaxe2x80x9d, London, 1993, recommends a peroral dosing of 200 mg three times daily to adults, 200 mg once daily for children up to 2 years and 200 mg twice daily for children aged 2 to 6 years.
Deutsche Apotheker Zeitung; 34; 1990 indicates that the maximum plasma level is reached 2 to 3 hours after oral administration. The same reference indicates 4% bioavailability upon oral administration.
Currently the mucolytic effect is achieved by inhalation or peroral administration of N-Acetyl-L-cysteine. The inhalation route can only be used for temporary relief and several dosings per day are necessary. Administration of N-Acetyl-L-cysteine through the oral route is hampered by a low bioavailability of the drug due to an extensive first-pass metabolism and side effects such as nausea and skin disorders, like rash.
The above disadvantages are removed or reduced upon administering N-Acetyl-L-cysteine transdermally.
N-Acetyl-L-cysteine is a fairly unstable drug in aqueous formulation. This could be improved by incorporation into a lipophilic medium like the one used in pressure sensitive adhesives, such as polyisobutylenes, acrylates and silicone derivatives.
Transdermal administration of N-Acetyl-L-cysteine is known from a few patents, e.g. from WO 95/00136 (ARNDT ET AL.) for treating hyperkeratosis, and WO 93/07903 (DECKNER ET AL.) wherein is disclosed certain cationic polymers which may improve transdermal penetration of a number of drugs, such as N-Acetyl-L-cysteine. Anyhow there is no patent which discloses transdermal administration of N-Acetyl-L-cysteine for achieving a mucolytic effect.
EP 0481294 (SPIRIG AG) discloses oral administration of acetylcysteine, but does not mention transdermal administration thereof.
Only sparse studies on skin permeation of N-Acetyl-L-cysteine have been reported in the literature with the aim to use N-Acetyl-L-cysteine as a model substance in connection with experiments to compare skin permeability between different animal species such as rat, rabbit, pig, monkey and man, see Methodius J. Bartek et al., xe2x80x9cSkin permeability in vivo in rat, rabbit, pig and manxe2x80x9d, 32nd Annual Meeting of the Society for Investigative Dermatology Inc., Boston, Mass., 1971, June 18-20, and Ronald C. Wester et al., Clin. Pharmacokinet., 1992;23(4):253-266. From inter alia the above Bartek reference it is evident that the transdermal pene-tration of N-Acetyl-L-cysteine hitherto was considered to be very low.
There is no literature reference which discloses transdermal administration of N-Acetyl-L-cysteine for achieving a mucolytic effect.
Hence the present invention being transdermally administered N-Acetyl-L-cysteine as mucolytic agent, as further described below, is both new and inventive over prior art.
The above mentioned disadvantages and side effects are removed or reduced when N-Acetyl-L-cysteine is administered transdermally.
Accordingly, a first object of the present invention is to provide a device for transdermal administration of N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, for achieving a mucolytic effect. The administration can be to a human being or to an animal. The mucolytic effect is for treating any kind of mucous and purulent expectorates, such as, but not exclusively, mucous and purulent expectorates occuring in association with upper and lower respiratory infections, including chronic bronchitis and asthma, and with cystic fibrosis, emphysema, tracheostomy and post-operative pulmonary complications. The pharmacological effect is primarily achieved by reduction of the viscosity for the mucous and purulent expectorates.
A second object of the invention is to provide use of a mucolytic compound comprising N-Acetyl-L-cysteine for the manufacture of a composition to be administered transdermally for treating mucous and purulent expectorates, primarily by decreasing their viscosity, or conditions associated with mucous and purulent expectorates.
A third object of the invention is to provide a method of treating diseases, in humans or animals, which are treatable with mucolytic agents by administering N-Acetyl-L-cysteine transdermally.
Other objects of the invention will become apparent to one skilled in the art, and still other objects will become apparent hereinafter.
The present invention relates to transdermal administration of N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof for achieving a mucolytic effect. This effect is primarily achieved through the systemic effect of N-Acetyl-L-cysteine whereby in the first place the viscosity of mucous and purulent expectorates is decreased. Anyhow, other mechanisms of actions are not excluded.